The mammalian Toll-like receptors (TLR) sense conserved molecules of microbial origin, including bacterial lipopolysaccharides (LPS), lipopeptides, glucans, flagellin, and nucleic acids. Poltorak, A. et al., Science 282:2085-2088, 1998; Takeuchi, O. et al., J. Immunol. 164:554-557, 2000; Takeuchi, O. et al., 13:933-940, 2001; Gantner, B. N. et al., J. Exp. Med. 197:1107-1117, 2003; Hayashi, F. et al., Nature 410:1099-1103, 2001; Hemmi, H. et al., Nature 408:740-745, 2000; Alexopoulou, L. et al., Nature 413:732-738, 2001; Diebold, S. S. et al., Science 303:1529-1531, 2004; Heil, F. et al., Science 303:1526-1529, 2004; Lund, J. M. et al., Proc. Natl. Acad. Sci U.S.A 101:5598-5603, 2004. While TLRs 1, 2, 4, and 6 are at least partly represented on the surface of mammalian cells, TLRs 3, 7, and 9, which detect dsRNA, ssRNA, and unmethylated DNA, respectively are predominantly or entirely intracellular receptors, residing within the endoplasmic reticulum (ER) and/or endosomes. Hemmi, H. et al., Nature 408:740-745, 2000; Alexopoulou, L. et al., Nature 413:732-738, 2001; Diebold, S. S. et al., Science 303:1529-1531, 2004; Heil, F. et al., Science 303:1526-1529, 2004; Lund, J. M. et al., Proc. Natl. Acad. Sci U.S.A 101:5598-5603, 2004; Matsumoto, M. et al., J. Immunol. 171:3154-3162, 2003; Funami, K. et al., Int. Immunol. 16:1143-1154, 2004; Ahmad-Nejad, P. et al., Eur. J. Immunol. 32:1958-1968, 2002; Leifer, C. A. et al., 173:1179-1183, 2004; Latz, E. et al., 5:190-198, 2004; Heil, F. et al., Eur. J. Immunol. 33:2987-2997, 2003.
TLRs mediate the great majority of phenomena associated with microbial infections, including the upregulation of costimulatory molecules that are required to initiate adaptive immune responses to peptides processed and presented by antigen-presenting cells of the host. Beutler, B. Nature 430:257-263, 2004. But the processing and presentation of antigens—whether endogenous or exogenous—occurs constitutively in the absence of infection and does not dependent upon TLR signaling. Moreover, where exogenous antigens are concerned, processing for class I MHC presentation (cross presentation) involves a series of biochemical events very different from those associated with processing for class II MHC presentation.